The complement system has been strongly implicated as a participant in the inflammatory component of human interstitial lung disease and in models of immunologic alveolitis. The cleavage fragments of C5 have been shown by us and others to initiate inflammation upon instillation into the lungs of experimental animals. We have recently obtained preliminary evidence that intact C5 is present in normal lungs and that C5-deficient mice do not mount a pulmonary inflammatory response to instilled immune complexes. Taken together, these observations have led us to suggest that pulmonary C5 and its cleavage products may play an important role in the induction of pulmonary inflammation. To pursue this suggestion we will 1) determine which C5 fragments are involved and examine their mode of action, 2) determine the origin of pulmonary C5 and how it may be cleaved in vivo, and 3) demonstrate that C5 fragments do indeed participate in pulmonary inflammation. Rabbits and congenic C5-deficient and -sufficient mice will be used. Purified rabbit C5 and C5 fragments (and C3) are available. Available assessment techniques for inflammation include histology, measurement of permeability and hemorrhage, of neutrophil and monocyte accumulation and of pulmonary function changes (in rabbits). A specific focus will be the possibility that pulmonary macrophages secrete C5 (to be examined in vitro and in vivo and by cell transfer in C5-deficient mice) and that when stimulated (e.g. by inhaled materials), secrete a protease(s) which cleaves the C5. If such a protease is secreted it will be identified and the conditions of its induction pursued. Assays will be established to detect C5 fragments in lavage fluids (radioimmunoassay) and to detect the previous effect of such fragments on lavaged inflammatory cells (stimulus specific desensitization). These techniques will be used to pursue the possible involvement of C5 fragments in experimental pulmonary inflammation, and eventually in selected human disease conditions. The study is designed to pinpoint the participation of C5 in the initiation and exacerbation of pulmonary inflammation but should also help elucidate basic inflammatory mediation processes.